Phase-dependent closed-loop deep brain stimulation of the fornix provides bidirectional manipulation of hippocampal theta oscillations

Abstract

Introduction

Alzheimer's disease (AD) has very limited treatment options and therapies to prevent or reverse neurodegeneration remain elusive. Deep brain stimulation (DBS), whereby high-frequency pulses of electricity are delivered continuously to a specific part of the brain, has been trialled as an experimental treatment for AD. In AD patients, continuous, high frequency DBS targeted to the fornix (fx-DBS) has been shown to be safe, but not reliably effective across patients. In movement disorders, high-frequency DBS is thought to act as a virtual lesion, disrupting pathophysiological activity. In AD, it may be more advantageous to use stimulation to reinforce or rebuild oscillatory activities that are disrupted by the disease process. A primary candidate for such a target is the hippocampal theta oscillation, which provides a temporal framework for mnemonic processing and is altered in rodent models of AD.

Material and methods

We applied closed-loop electrical stimulation to the fornix of rats traversing a linear track, triggered by different phases of the ongoing theta oscillation in the hippocampal local field potential (LFP) using the OscillTrack algorithm.

Results

Stimulation at different target phases could robustly suppress or amplify the theta oscillation, and these effects were significantly larger than those caused by open-loop replay of the same stimulation pattern. Amplification of the theta oscillation could be achieved irrespective of the locomotor speed of the animal, showing that it did not result from a secondary effect of behavioural change.

Conclusions

Our findings demonstrate that closed-loop fx-DBS is a viable method of modulating the amplitude of hippocampal theta oscillations that could be applied in human devices to provide a constructive intervention with the potential to boost memory circuit function in AD.